Gout is a common and excruciatingly painful inflammatory arthritis associated with hyperuricemia. Gout represents a metabolically-driven arthropathy that could be substantially controlled through dietary and lifestyle modifications. With the continued western lifestyle in the US, the prevalence and incidence of gout have increased over the last few decades and it is estimated that 3.9% of US adults (8.3 million individuals) have had gout according to the latest US NHANES data. This remarkable burden of gout is further complicated by its high level of cardiovascular (CV)-metabolic comorbidities (e.g., hypertension in 74% and obesity in 53% of cases) and their consequences (e.g., increased future risk of myocardial infarction and premature death). The current low-purine dietary approach to gout offers limited efficacy, palatability, and sustainability, and promotes increased consumption of refined carbohydrates and saturated fat that can actually worsen gout's CV-metabolic comorbidities by leading to insulin-resistance and increased levels of plasma glucose, triglycerides, and LDL-cholesterol. Therefore, there is an urgent need for a unifying, sustainable, and effective prevention strategy that holistically addresses both gout and its associated comorbidities. In fact, there are proven, effective dietary approaches to reduce CV-metabolic conditions (including obesity) that could also lower serum uric acid (SUA) levels and the risk of gout by lowering adiposity and insulin resistance. These existing approaches could potentially provide an ideal dietary strategy to reduce both the risk of gout and its associated CV-metabolic conditions. In this study, we will build upon our extensive experience with gout prevention research to examine the impact of these dietary approaches on the outcomes of both SUA and gout. We will investigate their effects on SUA levels using stored blood samples from 6 landmark randomized controlled trials of various dietary approaches to reduce CV-metabolic conditions (including the Mediterranean, Atkins, and DASH diets) (Aims 1-3). Through participation of the PIs of all 6 trials in this project, we will take full advantage of the original RCT designs and collected data. Further, we will evaluate their impact on the risk of gout based on 3 large prospective cohorts: the Nurses' Health Study (NHS) I (n=121,700 women), NHS II (n=116,430 younger women), and the Health Professionals Follow-up Study (HPFS; n=51,529 men) (Aim 4). We will take advantage of systematically collected high- quality data that have undergone rigorous validation including >3,200 confirmed cases of incident gout. These aims hold the potential to revolutionize our non-pharmacological urate-lowering approaches to hyperuricemia and gout by simultaneously investigating multiple candidate diets using a highly cost-effective study design. These measures will also comprehensibly address the major comorbidities associated with the rising disease burden of gout. With our extensive gout research experience combined with resourceful data access, we are in a unique and unparalleled position to address these key issues facing the field in the US and beyond.